Activation of Discoidin Domain Receptor 1 Isoform b with Collagen Up-Regulates Chemokine Production in Human Macrophages: Role of p38 Mitogen-Activated Protein Kinase and NF-κB

Wataru Matsuyama, Lihua Wang, William L. Farrar, Michel Faure, Teizo Yoshimura

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Macrophages produce an array of proinflammatory mediators at sites of inflammation and contribute to the development of inflammatory responses. Important roles for cytokines, such as IL-1 or TNF-α, and bacterial products, such as LPS, in this process have been well documented; however, the role for the extracellular matrix proteins, such as collagen, remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed during differentiation of human monocytes into macrophages, and the interaction of the DDR1b isoform with collagen facilitates their differentiation via the p38 mitogen-activated protein kinase (MAPK) pathway. In this study, we report that the interaction of DDR1b with collagen up-regulates the production of IL-8, macrophage inflammatory protein-α, and monocyte chemoattractant protein-1 in human macrophages in a p38 MAPK- and NF-κB-dependent manner. p38 MAPK was critical for DDR1b-mediated, increased NF-κB trans-activity, but not for IκB degradation or NF-κB nuclear translocation, suggesting a role for p38 MAPK in the modification of NF-κB. DDR1b-mediated IκB degradation was mediated through the recruitment of the adaptor protein Shc to the LXNPXY motif of the receptor and the downstream TNFR-associated factor 6/NF-κB activator 1 signaling cascade. Taken together, our study has identified NF-κB as a novel target of DDR1b signaling and provided a novel mechanism by which tissue-infiltrating macrophages produce large amounts of chemokines during the development of inflammatory diseases. Intervention of DDR1b signaling may be useful to control inflammatory diseases in which these proteins play an important role.

Original languageEnglish
Pages (from-to)2332-2340
Number of pages9
JournalJournal of Immunology
Volume172
Issue number4
Publication statusPublished - Feb 15 2004
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-akt
p38 Mitogen-Activated Protein Kinases
Chemokines
Protein Isoforms
Up-Regulation
Collagen
Macrophages
Shc Signaling Adaptor Proteins
Collagen Receptors
Macrophage Inflammatory Proteins
Extracellular Matrix Proteins
Interleukin-8
Interleukin-1
Monocytes
Cytokines
Inflammation
Discoidin Domain Receptor 1
Proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Activation of Discoidin Domain Receptor 1 Isoform b with Collagen Up-Regulates Chemokine Production in Human Macrophages : Role of p38 Mitogen-Activated Protein Kinase and NF-κB. / Matsuyama, Wataru; Wang, Lihua; Farrar, William L.; Faure, Michel; Yoshimura, Teizo.

In: Journal of Immunology, Vol. 172, No. 4, 15.02.2004, p. 2332-2340.

Research output: Contribution to journalArticle

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